Human postnatal dental mesenchymal stem cells (DMSCs) are unique precursor populations which are isolated from the dental pulp, root apex and periodontal ligament based on the primary characteristics of mesenchymal stem cells (MSCs) from bone marrow. DMSCs offer an attractive cell therapy for the regeneration and repair of dental and craniofacial tissue defects due to their convenient isolation and lack of immunogenicity. However, very little is known with respect to the molecular and epigenetic events that control DMSC commitment and differentiation to dental and craniofacial bone tissues. DNA and histone demethylases are newly-identified enzymes for removing DNA and histone methyl markers associated with gene activation or silencing. Using molecular and epigenetic approaches, we found that estrogen potently promoted odonto/osteogenic differentiation of DMSCs by inducing the histone lysine (K)-specific demethylase 6B (KDM6B) and DNA demethylase Ten-Eleven Translocation 2 (TET2). Contrary to estrogen, pro-inflammatory cytokines such as tumor necrosis factor (TNF) activated nuclear factor-kappa B (NF-?B) to inhibit DMSC differentiation. Very intriguingly, we observed that estrogen abolished TNF inhibition of DMSC differentiation by blocking NF-?B. In the realm of therapeutic dental and craniofacial tissue regeneration, the defective or injured tissues are frequently inflamed with pro-inflammatory cytokines. It is critical to control inflammation in order to achieve a successful regenerative therapy. In this competing renewal, based on our novel findings, we hypothesize that estrogen epigenetically promotes DMSC differentiation by histone and DNA demethylation while simultaneously inhibiting NF-?B and inflammation. To test our hypothesis, we proposed the following three specific aims: 1) Determine how estrogen induces KDM6B to enhance odonto/osteogenic differentiation of DMSCs by demethylating repressive H3K27me3 marks; 2) Determine how estrogen induces TET2 to enhance DMSC differentiation by DNA demethylation; and 3) Determine whether estrogen circumvents TNF inhibition of DMSC differentiation and promotes DMSC-mediated craniofacial bone regeneration and repair in vivo. Taken together, identifying whether estrogen not only promotes odonto/osteogenesis of DMSC but also inhibits inflammation would be a major therapeutic advance. Our work may help to develop novel strategies for promoting dental and craniofacial tissue regeneration and repair and for controlling inflammation.